Mendelian gene identification through mouse embryo viability screening
Authors: Pilar Cacheiro, Carl Henrik Westerberg, Jesse Mager, Mary E. Dickinson, Lauryl M. J. Nutter, Violeta Muñoz-Fuentes, Chih-Wei Hsu, Ignatia B. Van den Veyver, Ann M. Flenniken, Colin McKerlie, Stephen A. Murray, Lydia Teboul, Jason D. Heaney, K. C. Kent Lloyd, Louise Lanoue, Robert E. Braun, Jacqueline K. White, Amie K. Creighton, Valerie Laurin, Ruolin Guo, Dawei Qu, Sara Wells, James Cleak, Rosie Bunton-Stasyshyn, Michelle Stewart, Jackie Harrisson, Jeremy Mason, Hamed Haseli Mashhadi, Helen Parkinson, Ann-Marie Mallon, John R. Seavitt, Angelina Gaspero, Uche Akoma, Audrey Christiansen, Sowmya Kalaga, Lance C. Keith, Melissa L. McElwee, Leeyean Wong, Tara Rasmussen, Uma Ramamurthy, Kiran Rajaya, Panitee Charoenrattanaruk, Qing Fan-Lan, Lauri G. Lintott, Ozge Danisment, Patricia Castellanos-Penton, Daniel Archer, Sara Johnson, Zsombor Szoke-Kovacs, Kevin A. Peterson, Leslie O. Goodwin, Ian C. Welsh, Kristina J. Palmer, Alana Luzzio, Cynthia Carpenter, Coleen Kane, Jack Marcucci, Matthew McKay, Crystal Burke, Audrie Seluke, Rachel Urban, John C. Ambrose, Prabhu Arumugam, Roel Bevers, Marta Bleda, Freya Boardman-Pretty, Christopher R. Boustred, Helen Brittain, Matthew A. Brown, Mark J. Caulfield, Georgia C. Chan, Greg Elgar, Adam Giess, John N. Griffin, Angela Hamblin, Shirley Henderson, Tim J. P. Hubbard, Rob Jackson, Louise J. Jones, Dalia Kasperaviciute, Melis Kayikci, Athanasios Kousathanas, Lea Lahnstein, Sarah E. A. Leigh, Ivonne U. S. Leong, Javier F. Lopez, Fiona Maleady-Crowe, Meriel McEntagart, Federico Minneci, Jonathan Mitchell, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Peter O’Donovan, Chris A. Odhams, Christine Patch, Mariana Buongermino Pereira, Daniel Perez-Gil, John Pullinger, Tahrima Rahim, Augusto Rendon, Tim Rogers, Kevin Savage, Kushmita Sawant, Richard H. Scott, Afshan Siddiq, Alexander Sieghart, Samuel C. Smith, Alona Sosinsky, Alexander Stuckey, Mélanie Tanguy, Ana Lisa Taylor Tavares, Ellen R. A. Thomas, Simon R. Thompson, Arianna Tucci, Matthew J. Welland, Eleanor Williams, Katarzyna Witkowska, Suzanne M. Wood, Magdalena Zarowiecki, Damian Smedley
Journal: Genome Medicine (2022)

Abstract Background The diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful. A full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property. Methods Here we further dissected this spectrum by assessing the embryonic stage at which homozygous loss-of-function results in lethality in mice from the International Mouse Phenotyping Consortium, classifying the set of lethal genes into one of three windows of lethality: early, mid, or late gestation lethal. We studied the correlation between these windows of lethality and various gene features including expression across development, paralogy and constraint metrics together with human disease phenotypes. We explored a gene similarity approach for novel gene discovery and investigated unsolved cases from the 100,000 Genomes Project. Results We found that genes in the early gestation lethal category have distinct characteristics and are enriched for genes linked with recessive forms of inherited metabolic disease. We identified several genes sharing multiple features with known biallelic forms of inborn errors of the metabolism and found signs of enrichment of biallelic predicted pathogenic variants among early gestation lethal genes in patients recruited under this disease category. We highlight two novel gene candidates with phenotypic overlap between the patients and the mouse knockouts. Conclusions Information on the developmental period at which embryonic lethality occurs in the knockout mouse may be used for novel disease gene discovery that helps to prioritise variants in unsolved rare disease cases.